Thayer Amanda, Murataeva Natalia, Delcroix Vanessa, Wager-Miller Jim, Makarenkova Helen P, Straiker Alex
The Gill Center for Biomolecular Science, Indiana University, Bloomington, Indiana, United States.
Department of Psychological and Brain Sciences, Indiana University, Bloomington, Indiana, United States.
Invest Ophthalmol Vis Sci. 2020 Aug 3;61(10):48. doi: 10.1167/iovs.61.10.48.
Aqueous deficiency dry eye (ADDE) is a chronic condition affecting millions, with symptoms ranging from a dry itchiness to blurred vision and accompanied by an increased risk of eye infections. ADDE typically arises from disorders of the lacrimal gland that produces tears necessary for eye lubrication. Cannabis users frequently report dry eye, but the basis for this is unknown. If the effects occur via the endogenous cannabinoid signaling system, then this may represent a novel mechanism for the regulation of tearing.
We examined expression of cannabinoid CB1 receptors in the lacrimal gland using immunohistochemistry, Western blotting, and PCR and tested tetrahydrocannabinol (THC) regulation of tearing in wild-type and CB1-null mice.
We now report that CB1 receptors are expressed in the axons of cholinergic neurons innervating the lacrimal gland. Little if any staining is seen in lacrimal gland epithelial cells (acinar and ductal) or myoepithelial cells (MECs). Activation of CB1 receptors by THC or the cannabinoid agonist CP55940 reduces tearing in male mice. In female mice, THC has no effect, but CP55940 increases tearing. In both sexes, the effect of CP55940 is absent in CB1 knockout mice. CB1 mRNA and protein levels are approximately four- to fivefold higher in males than females. In male knockouts, THC increases tearing, suggesting that THC also acts through different receptors.
Our results suggest a novel, albeit sex-dependent, physiologic basis for the dry eye symptoms experienced by cannabis users: activation of neuronal CB1 receptors in the lacrimal gland reduces tearing.
水液缺乏型干眼症（ADDE）是一种影响数百万人的慢性疾病，症状从眼部干痒到视力模糊不等，并伴有眼部感染风险增加。ADDE通常源于泪腺紊乱，泪腺负责产生眼部润滑所需的泪水。大麻使用者经常报告有干眼症，但其中的原因尚不清楚。如果这种影响是通过内源性大麻素信号系统发生的，那么这可能代表了一种调节泪液分泌的新机制。
我们使用免疫组织化学、蛋白质印迹法和聚合酶链反应检测了泪腺中大麻素CB1受体的表达，并测试了野生型和CB1基因敲除小鼠中四氢大麻酚（THC）对泪液分泌的调节作用。
我们现在报告，CB1受体表达于支配泪腺的胆碱能神经元的轴突中。在泪腺上皮细胞（腺泡和导管）或肌上皮细胞（MECs）中几乎看不到染色。THC或大麻素激动剂CP55940激活CB1受体会减少雄性小鼠的泪液分泌。在雌性小鼠中，THC没有作用，但CP55940会增加泪液分泌。在两性中，CB1基因敲除小鼠对CP55940均无反应。CB1的mRNA和蛋白质水平在雄性中比雌性高约四到五倍。在雄性基因敲除小鼠中，THC会增加泪液分泌，这表明THC也通过不同的受体起作用。
我们的结果表明，大麻使用者所经历的干眼症症状存在一种新的、尽管与性别有关的生理基础：泪腺中神经元CB1受体的激活会减少泪液分泌。
